Renal cell carcinoma (RCC) is a major health issue. While localized disease can be cured surgically, there is no effective treatment for metastatic disease. The development of therapy awaits understanding of the molecular pathways that underlie RCC carcinogenesis. Using genomic profiling of conventional RCC patient matched specimens, we identified aberrations in the transforming growth factor beta (TGFbeta) pathway. We observed loss of type III TGFbeta receptor (TbetaR3) in all samples. This suggests that loss of TbetaR3 is an early, sentinel event in the genesis of RCC. This is the first clear demonstration linking loss of TbetaR3 to a disease state. We also observed loss of type II TGFbeta receptor (TbetaR2) in metastatic RCC's. These data suggest that aberrations in TGFbeta signaling are important in RCC carcinogenesis and progression, and are mediated through down regulation of TbetaR. We hypothesize that loss of TbetaR3 promotes RCC tumorigenesis through dysregulation of TGFbeta signaling, mediated through Smad dependent and/or independent mechanisms. Our preliminary data also support the hypothesis that TbetaR3 has growth inhibitory activity independent of TGFbeta signaling and TbetaR2. These hypotheses will be tested in models of RCC, in vitro and in vivo, through the following specific aims: 1) We will test the hypothesis that TbetaR3 inhibits cell proliferation in RCC, in vitro, through both Smad dependent and independent mechanisms. We will further test whether TbetaR3 growth inhibition is mediated through TGFbeta/TbetaR2 independent pathways through interaction with, as yet, unknown intracellular proteins. 2) We will test the hypothesis that TbetaR3 inhibits tumorigenicity in vivo, using relevant animal models of RCC. We will test the efficacy of adenoviral gene therapy targeting TbetaR. 3) We will test the hypothesis that TbetaR3 is silenced in RCC through transcriptional regulation of the TbetaR3 promoter. Completion of these studies will define the role of TbetaR3 loss in RCC carcinogenesis, the function of TbetaR3 in normal renal biology and carcinogenesis, and the mechanism of regulation of TbetaR3 in RCC biology.